Pancreatic cancer (PC) is a highly metastatic and therapy-resistant malignancy with patients presenting with local and distant metastases at the time of diagnosis. The metastatic lesions while still undetectable contribute to the lethality of te disease and hence should be treated effectively. Antibodies directed against tumor antigens are ideal vehicles for delivering cytotoxic agents including therapeutic radionuclides to the known and occult metastatic cancer cells and can be a promising therapeutic option for treating PC. However, pancreatic tumors present a complex and highly obstructive microenvironment that is characterized by insufficient and heterogeneous tumor blood flow and extensive desmoplasia. Cell surface mucin, MUC4, is promising target for PC therapy due to its specific overexpression in tumor that correlates positively with disease progression and negatively with patient survival. Monoclonal antibody MAb 8G7, due to its reactivity to a repetitive epitope on MUC4, can potentially serve as a highly efficient targeting agent for PC. The central hypothesis of this proposal is: MUC4 is a novel molecular target for targeted radionuclide therapy (TRT) of lethal pancreatic cancer and selective modulation of tumor microenvironment can improve the delivery and enhance the therapeutic efficacy of MUC4-targeted radiopharmaceuticals. The overall objective of the proposed studies is to determine the utility of targeting pancreatic cancer with novel radiolabeled anti-MUC4 antibodies in combination with rationally-selected specific modulators of tumor microenvironment (TME). Tumor vasculature is characterized by structural and functional anomalies as compared to normal vasculature and these differences result in differential responses when the normal and tumor vasculature are exposed to various vasoactive agents. Modulation of tumor stromal compartment can be achieved by selectively targeting the signaling pathways that regulate various components of tumor stroma. Three specific aims are proposed: 1) Evaluation of MUC4 as a target for TRT of PC; 2) Selective Modulation of tumor microenvironment for improved delivery of radiopharmaceuticals; and 3) Determine the therapeutic efficacy of MUC4 and TME targeted combination therapy. Aim 1 will provide information about the efficiency of anti-MUC4 MAb for targeting PC in vivo and characterize the MAb in terms of biodistribution and pharmacokinetics. Further, the studies will allow us to determine which therapeutic radionuclide is compatible with anti-MUC4 MAb. Aim 2 will evaluate a combination of tumor-selective agents for their ability to improve TME in xenograft and autochthonous tumors for enhanced delivery of radiopharmaceuticals. Aim 3 will allow us to determine if the improved delivery, distribution and retention of radiolabeled antibodies translates to improved therapeutic efficacy. The proposed studies represent the first comprehensive effort to overcome physiological barriers for macromolecular radiopharmaceuticals and utilize clinically relevant transgenic mouse models of PC. The preclinical results obtained from the proposed study will form the basis of clinical trial in PC patients.